Re: 재생의학 중간엽 줄기세포의 임상적용 2022 리뷰논문..

[문형철]

• Review
• Open access
• Published: 28 July 2022

Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review

• Ria Margiana, 
• Alexander Markov, 
• Angelina O. Zekiy, 
• Mohammed Ubaid Hamza, 
• Khalid A. Al-Dabbagh, 
• Sura Hasan Al-Zubaidi, 
• Noora M. Hameed, 
• Irshad Ahmad, 
• R. Sivaraman, 
• Hamzah H. Kzar, 
• Moaed E. Al-Gazally, 
• Yasser Fakri Mustafa & 
• Homayoon Siahmansouri 

Stem Cell Research & Therapy volume 13, Article number: 366 (2022) Cite this article

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Abstract

The multipotency property of mesenchymal stem cells (MSCs) has attained worldwide consideration because of their immense potential for immunomodulation and their therapeutic function in tissue regeneration. MSCs can migrate to tissue injury areas to contribute to immune modulation, secrete anti-inflammatory cytokines and hide themselves from the immune system. Certainly, various investigations have revealed anti-inflammatory, anti-aging, reconstruction, and wound healing potentials of MSCs in many in vitro and in vivo models. Moreover, current progresses in the field of MSCs biology have facilitated the progress of particular guidelines and quality control approaches, which eventually lead to clinical application of MSCs. In this literature, we provided a brief overview of immunoregulatory characteristics and immunosuppressive activities of MSCs. In addition, we discussed the enhancement, utilization, and therapeutic responses of MSCs in neural, liver, kidney, bone, heart diseases, and wound healing.

요약

중간엽 줄기세포(MSC)의 다능성은 

면역 조절에 대한 막대한 잠재력과 조직 재생에 대한 치료 기능으로 인해 

전 세계적으로 주목받고 있습니다. 

MSC는 

조직 손상 부위로 이동하여 

면역 조절에 기여하고 

항염증 사이토카인을 분비하며 

면역 체계로부터 자신을 숨길 수 있습니다. 

MSCs can migrate to tissue injury areas to contribute to

immune modulation,

secrete anti-inflammatory cytokines and

hide themselves from the immune system

물론 다양한 연구를 통해 

많은 시험관 및 생체 내 모델에서 

MSC의 항염증, 노화 방지, 재건 및 상처 치유 잠재력이 밝혀졌습니다. 

또한, 현재 MSC 생물학 분야의 발전은 

특정 가이드라인과 품질 관리 접근법의 발전을 촉진하여 

결국 MSC의 임상 적용으로 이어지고 있습니다. 

이 문헌에서는 

MSC의 면역 조절 특성과 면역 억제 활동에 대한 간략한 개요를 제공했습니다. 

또한 

신경, 간, 신장, 뼈, 심장 질환 및 상처 치유에서 

MSC의 향상, 활용 및 치료 반응에 대해 논의했습니다.

Introduction

In the last decade, stem cells are increasingly applied as a therapeutic method for numerous disorders. Stem cell therapy, traditionally applied for hematopoietic disorders, nonetheless, is now established for the treatment of non-hematologic disorders [1, 2].

Accumulating evidence has shown that mesenchymal stem cells (MSCs) offer an encouraging option for cell treatment and reconstruction of human tissues because of their differentiation multipotency, self‐renewal capacity, long‐term ex vivo proliferation, paracrine potentials, and immunoregulatory effect [3]. Furthermore, MSCs have the capability to support the progression and differentiation of other stem cells. They can release bioactive molecules, which is a key benefit in tissue regeneration [4, 5]. These properties result in progression of treatments for a wide range of diseases, such as diseases affecting the bone, neuron, lung, liver, heart, kidney, etc. [4]. Due to these features, it is obvious that MSCs will hold a major therapeutic role in clinical trials. Because of these properties, we provided a general overview of the latest trials that studied the effectiveness of MSCs in several diseases such as neural, liver, kidney, bone, heart diseases, and wound healing.

소개

지난 10년 동안 줄기세포는 다

양한 질환의 치료 방법으로 점점 더 많이 적용되고 있습니다.

전통적으로

조혈 질환에 적용되던 줄기세포 치료는

이제 비혈액 질환의 치료에도 적용되고 있습니다[1, 2].

축적된 증거에 따르면

중간엽 줄기세포(MSC)는

분화 다능성,

자기 재생 능력,

장기 생체 외 증식,

파라크린 잠재력 및 면역 조절 효과로 인해

세포 치료 및 인체 조직 재건을 위한 고무적인 옵션을 제공합니다 [3].

Accumulating evidence has shown that

mesenchymal stem cells (MSCs) offer an encouraging option for cell treatment and reconstruction of human tissues

because of their

differentiation multipotency,

self‐renewal capacity,

long‐term ex vivo proliferation,

paracrine potentials, and

immunoregulatory effect

또한,

중간엽줄기세포는

다른 줄기세포의 진행과 분화를 지원할 수 있는 능력을 가지고 있습니다.

이들은

조직 재생의 주요 이점인

생리 활성 분자를 방출할 수 있습니다 [4, 5].

이러한 특성으로 인해

뼈, 신경세포, 폐, 간, 심장, 신장 등에 영향을 미치는 질병 등

광범위한 질병에 대한 치료가 진행됩니다. [4].

이러한 특성으로 인해

MSC가 임상시험에서 중요한 치료적 역할을 할 것은 분명합니다.

이러한 특성으로 인해

신경, 간, 신장, 뼈, 심장 질환 및 상처 치유와 같은 여러 질병에 대한 MSC의 효과를 연구한

최신 임상시험에 대한 전반적인 개요를 제공했습니다.

Stem cells in regenerative medicine

In the last years, numerous studies have demonstrated that cellular therapy has exhibited great development in both in vitro and in vivo researches. Stem cells have the capability to self-renew, and also to differentiate into all cell types and are involved in physiological regeneration [6].

There are multiple stem cell sources of adult and pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) for tissue regeneration. PSCs have a high potential for pluripotency and self-renewal, which makes these cells an important option for treatment of diseases. However, there are ethical issues when using these cells, in which ESCs are separated from blastocyst-stage embryos, requiring destruction of the embryo [7,8,9]. The results of studies have revealed the regenerative ability of iPSCs in preclinical setting and conducted the first clinical study for treatment of age-associated with macular deterioration [10, 11]. Nonetheless, the tumorigenicity risk remains unsolved. Because of these limitations, researchers began to investigate adult stem cells, the multipotent stem cells found in tissues and organs of adults. Various investigations have reported that stem cell therapy can regenerate and repair injured organs in vivo, including bone repair, cutaneous wound, pulpitis, and ischemic cardiac tissue through stem cell differentiation and production of new particular cells [12,13,14,15]. Moreover, some investigations have demonstrated that cultured adult stem cells release many molecular factors with anti-apoptotic, immunoregulatory, angiogenic, and chemoattractant features that stimulate regeneration [16,17,18]. Hematopoietic stem cells (HSCs) and MSCs are part of adult stem cells, which are the most widely used, generally because they can be isolated from individuals in diseased conditions.

재생 의학의 줄기세포

지난 몇 년 동안 수많은 연구를 통해

세포 치료가 시험관 내 연구와 생체 내 연구 모두에서

큰 발전을 이루었음이 입증되었습니다.

줄기세포는

자가 재생 능력이 있고

모든 세포 유형으로 분화할 수 있으며

생리적 재생에 관여합니다[6].

조직 재생을 위한 줄기세포에는

배아줄기세포(ESC), 유도만능줄기세포(iPSC) 등

성체줄기세포와

만능줄기세포(PSC) 등 다양한 줄기세포 공급원이 있습니다.

There are multiple stem cell sources of adult and pluripotent stem cells (PSCs) such as

embryonic stem cells (ESCs) and

induced pluripotent stem cells (iPSCs) for tissue regeneration.

PSCs have a high potential for pluripotency and self-renewal, which makes these cells an important option for treatment of diseases.

PSC는 만능성과 자가 재생 가능성이 높기 때문에 질병 치료를 위한 중요한 옵션이 될 수 있습니다.

그러나 이러한 세포를 사용할 때는

배반포기 단계의 배아에서 분리하여

배아를 파괴해야 하는 윤리적 문제가 있습니다 [7,8,9].

연구 결과 전임상 환경에서

iPSC의 재생 능력이 밝혀졌고

노화와 관련된 황반변성 치료를 위한 최초의 임상 연구가 수행되었습니다 [10, 11].

그럼에도 불구하고

종양원성 위험은

여전히 해결되지 않은 과제로 남아 있습니다.

Because of these limitations, researchers began to investigate

adult stem cells, the

multipotent stem cells found in tissues and organs of adults

이러한 한계로 인해 연구자들은

성인의 조직과 장기에서 발견되는

다능성 줄기세포인 성체 줄기세포를 조사하기 시작했습니다.

Various investigations have reported that stem cell therapy can regenerate and repair injured organs in vivo, including bone repair, cutaneous wound, pulpitis, and ischemic cardiac tissue through stem cell differentiation and production of new particular cells [12,13,14,15]

다양한 연구에서

줄기세포 치료가

줄기세포 분화 및 새로운 특정 세포의 생산을 통해

뼈 복구, 피부 상처, 치수염, 허혈성 심장 조직 등

생체 내에서 손상된 장기를 재생 및 복구할 수 있다고 보고했습니다[12,13,14,15].

또한 일부 연구에서는

배양된 성체 줄기세포가

재생을 촉진하는

항세포사멸, 면역 조절, 혈관 신생 및 화학 유인 기능을 가진

많은 분자 인자를 방출한다는 사실이 입증되었습니다 [16,17,18].

Hematopoietic stem cells (HSCs) and MSCs

are part of adult stem cells,

which are the most widely used, generally because they can be isolated from individuals in diseased conditions.

조혈 줄기세포(HSC)와 중간엽 줄기세포는

성체 줄기세포의 일부로,

일반적으로 질병이 있는 개인으로부터 분리할 수 있기 때문에

가장 널리 사용됩니다.

Mesenchymal stem cell

In the late 1960s, Friedenstein and colleagues discovered MSCs as multipotent stem cells for the first time [19]. MSCs are non-hematopoietic cells and have the capability to differentiate into various lineage including mesodermal (adipocytes, osteocytes, and chondrocytes), ectodermal (neurocytes), and endodermal lineage (hepatocytes) [20, 21]. At the beginning, it was thought that MSCs are “stromal” cells instead of stem cells [22]. Several investigators tried to alter the name of MSCs to medicinal signaling cells due to their function in secretion of some metabolites molecules in the sites of diseases, injuries, and inflammations [23, 24]. After that, some studies have stated that MSCs can release prostaglandin E2 (PGE2), which plays a major role in the self-renewal ability, immunomodulation of MSCs, and generating a cascade of events, that demonstrates the stemness of MSCs [25]. Therefore, the term mesenchymal stem cells is justified.

MSCs chiefly found in the bone marrow (BM) possess the ability of self-renewal and also display multilineage differentiation [8, 26, 27]. They were obtained from various tissues and organs including BM, adipose tissue, Wharton’s jelly, peripheral blood, umbilical cord, placenta, amniotic fluid, and dental pulp [3, 28,29,30]. MSCs can express a wide range of surface markers and cytokine profiles according to the origin of isolation [31]. Nevertheless, the common characterization markers of MSCs are CD73, CD105, CD90 and lacking expression‎ of CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA-DR [32,33,34]. During the last decades, MSCs have shown various biological roles such as multilineage differentiation, immunomodulation, angiogenesis, anti-apoptotic and anti-fibrotic activity, chemo-attraction, and tissue repair development [35,36,37]. The MSCs have broad properties that make them a suitable source for cell therapy, such as stemness potency, easily isolation from different sources, they can be rapidly expanded in a large scale for clinical use, have less ethical issues as compared to ESCs, unlike iPSCs, MSCs transport a lower risk of teratoma formation, and they are beneficial for a wide scale of therapeutic applications due to their capability to migrate to injured tissue through chemo-attraction [38,39,40]. In addition, MSCs can release a variety of bioactive components including proteins, growth factors chemokines, microRNAs (miRNAs), and cytokines which can suggest their acceptable application [41].

중간엽 줄기세포

1960년대 후반,

프리덴슈타인과 동료들은

중간엽줄기세포를 다능성 줄기세포로 처음 발견했습니다[19].

MSC는

비조혈 세포이며

중배엽(지방세포, 조골세포, 연골세포),

외배엽(신경세포),

내배엽(간세포) 등

다양한 계통으로 분화할 수 있는 능력을 가지고 있습니다[20, 21].

처음에는

중간엽줄기세포가 줄기세포가 아닌

“기질” 세포라고 생각했습니다[22].

몇몇 연구자들은

질병, 부상 및 염증 부위에서 일부 대사 산물 분자를 분비하는 기능으로 인해

MSC의 이름을 의약 신호 세포로 변경하려고 시도했습니다 [23, 24].

그 후 일부 연구에서는

중간엽줄기세포가

프로스타글란딘 E2(PGE2)를 방출할 수 있으며,

이는 중간엽줄기세포의 자기 재생 능력, 면역조절 및 일련의 사건 발생에 중요한 역할을 하여

중간엽줄기세포의 줄기세포성을 입증한다고 밝혔습니다[25].

따라서

중간엽 줄기세포라는 용어는

정당합니다.

주로

골수(BM)에서 발견되는

MSC는 자기 재생 능력을 가지고 있으며

다계대 분화도 나타냅니다 [8, 26, 27].

BM, 지방 조직, 와튼 젤리, 말초 혈액, 탯줄, 태반, 양수, 치아 치수 등

다양한 조직과 장기에서 얻었습니다 [3, 28,29,30].

MSC는

분리 출처에 따라 광범위한 표면 마커와 사이토카인 프로파일을 발현할 수 있습니다 [31].

그럼에도 불구하고,

MSC의 일반적인 특성화 마커는

CD73, CD105, CD90이며 CD45, CD34, CD14 또는

CD11b, CD79α 또는 CD19 및 HLA-DR의 발현이 부족합니다 [32,33,34].

During the last decades,

MSCs have shown various biological roles such as

multilineage differentiation,

immunomodulation,

angiogenesis,

anti-apoptotic and

anti-fibrotic activity,

chemo-attraction, and

tissue repair development

지난 수십 년 동안

MSC는

다계대 분화, 면역 조절, 혈관 신생, 항세포사멸 및 항섬유화 활성, 화학 유인 및 조직 복구 발달과 같은 다

양한 생물학적 역할을 보여주었습니다 [35,36,37].

줄기세포는

줄기세포 효능,

다양한 공급원으로부터의 쉬운 분리,

임상 사용을 위해 대규모로 빠르게 확장할 수 있고,

iPSC와 달리 윤리적 문제가 적으며,

기형종 형성의 위험이 적고,

화학 유인을 통해 손상된 조직으로 이동하는 능력으로 인해

광범위한 치료 응용에 유리한 특성을 가지고 있습니다

https://www.nature.com/articles/s41392-024-01809-0

유도만능줄기세포(iPSC) 기술은 체외 연구를 변화시켰으며 재생의학을 발전시킬 큰 가능성을 가지고 있습니다. iPSC는 거의 무제한으로 확장할 수 있고 유전공학이 가능하며 대부분의 체세포 유형으로 분화할 수 있으며, 인간 발달 및 질병 모델, 약물 스크리닝, 세포 치료제 개발에 널리 적용되어 왔습니다. 이 리뷰에서는 iPSC 분야의 주요 발전 사항을 간략히 살펴보고 체외 모델링 및 치료 응용 분야에 대한 iPSC 기술의 엄청난 다용도성을 강조합니다. 먼저 리프로그래밍을 위한 체세포 핵의 잠재력을 밝혀내고 iPSC의 성공적인 생성으로 이어진 중추적인 발견에 대해 논의합니다. 체세포 리프로그래밍의 분자 메커니즘과 역학은 물론 만능성을 유도하는 데 사용할 수 있는 다양한 방법을 고려합니다. 이어서 단일 세포 유형의 단일 배양에서 복잡한 3차원 오가노이드에 이르기까지 다양한 iPSC 기반 세포 모델과 이러한 모델이 인간 발달과 질병의 메커니즘을 규명하는 데 어떻게 적용될 수 있는지에 대해 논의합니다. 신경계 질환, 코로나바이러스 감염증 2019(COVID-19), 암의 사례를 통해 iPSC 유래 세포를 사용하여 모델링할 수 있는 질병별 표현형의 다양성을 강조합니다. 또한 고처리량 약물 스크리닝 및 약물 독성 연구에서 iPSC 유래 세포 모델을 어떻게 사용할 수 있는지 살펴봅니다. 마지막으로 자가 및 동종 iPSC 기반 세포 치료제의 개발 과정과 인간의 질병을 완화할 수 있는 잠재력에 대해 논의합니다.

[38,39,40]와 같이 세포 치료에 적합한 광범위한 특성을 가지고 있습니다.

또한,

MSC는

단백질, 성장 인자 케모카인, 마이크로RNA(miRNA), 사이토카인을 포함한

다양한 생리 활성 성분을 방출할 수 있어

그 적용 가능성을 시사할 수 있습니다[41].

The biological roles of MSCs

MSCs have the ability to inhibit the immune response in inflammatory cytokine-rich situations, including infections, wounds, or immune-mediated disorders. These immunomodulatory properties were discovered in preclinical and clinical trials, where MSCs effectively suppressed T cell activation and proliferation along with stimulation of macrophages shift from M1 to M2 [42,43,44]. This specific performance of MSCs in the presence and absence of inflammatory mediators is termed MSC polarization. MSCs have the ability to migrate to damaged areas after systemic infusion and consequently exert a beneficial effect by various mechanisms, chiefly immunoregulation, and angiogenesis [45, 46]. Although the related mechanism-mediated MSC immunosuppression has not been entirely clear, it appears that cellular interaction, accompanied by many factors, performs the principal function in this process. In the presence of high levels of inflammatory cytokines, e.g., TNF-α and IFN-γ, MSCs release several cytokines including TGF-β and hepatocyte growth factor (HGF) and produce soluble factors including indoleamine 2,3-dioxygenase (IDO), PGE2, and nitric oxide (NO). These mediators suppress T effector cells and enhance the expression‎ of FOXP3, CTLA4, and GITR in regulatory T cells (Tregs) to increase their immunomodulation effects [47,48,49]. Moreover, cell-to-cell communication facilitates the stimulation of Tregs by cytokine-primed MSCs [50]. Overexpression‎ of inducible co-stimulator ligands (ICOSL) induces the stimulation of efficient Tregs [51].

In addition, MSCs can enhance the generation of Treg cells indirectly. According to the literature, MSCs stimulate M2 macrophage and alter the phenotype through secretion of extracellular vesicles in an in vitro study [52]. Also, M2 cells that are activated by MSCs express CCL-18 and induce Treg cells [53]. Moreover, MSCs increase the expression‎ of cyclooxygenase 2 (COX2) and IDO, resulting in expression‎ of CD206 and CD163 in M2 cells, as well as enhance the expression‎ of IL-6 and IL-10 in the microenvironment [54]. The overexpression‎ of IL-10 that is produced by dendritic cells (DCs) and M2 cells upon MSCs co-culture leads to further immunomodulation via inhibition of effector T cells [55, 56]. Furthermore, the secretion of IDO from MSCs can induce the proliferation, activation, and IgG releasing of B cells, thereby suppressing T effector cells [57, 58].

One of the typical properties of MSCs is their multipotency capacity in which these stem cells are able to differentiate into a number of tissues in vitro [59]. Chondrogenic differentiation of MSCs in vitro occurs commonly via culturing them in the existence of TGF-β1 or TGF-β3, IGF-1, FGF-2, or BMP-2 [60,61,62,63]. MSC differentiation into chondroblasts is characterized by the increasing of various genes such as collagen type II, IX, aggrecan, and proliferation of chondroblast cell morphology. During the process of chondrogenesis, FGF-2 promotes the MSCs induced with TGF-β1 or TGF-β3 and/ or IGF-1 [64]. According to the literature works, several molecular pathways such as hedgehog, Wnt/β-catenin, TGF-βs, BMPs, and FGFs can regulate chondrogenesis [65]. In addition, MSCs can exert the osteogenesis function by inducing MSCs with ascorbic acid, β-glycerophosphate, vitamin D3, and/or BMP-2, BMP-4, BMP-6, and BMP-7 [66].

One of the major abilities of MSCs is anti-fibrotic activity. These cells can differentiate into various cell lineages such as hepatocytes, both in vivo and in vitro [67]. MSCs contain multiple trophic factors which induce cells and matrix remodeling to stimulate progenitor cells and the recovery of damaged cells. MSCs can decrease myofibroblasts and reverse the fibrotic activity of injured tissues [68]. Furthermore, these cells release pro-angiogenic factors including VEGF, IGF-1, and anti-inflammatory factors that participate in the recovery of tissue function. For instance, MSCs can increase neovascularization of ischemic myocardium through VEGF in a mice model of heart disease [69]; also, IGF-1 exerts an advantageous effect on the survival and proliferation of cardiomyocytes [70].

중간엽줄기세포의 생물학적 역할

중간엽줄기세포는

감염, 상처 또는 면역 매개 질환 등 염

증성 사이토카인이 풍부한 상황에서

면역 반응을 억제하는 능력이 있습니다.

이러한 면역 조절 특성은

전임상 및 임상 시험에서 발견되었으며,

MSC는 대식세포가 M1에서 M2로 전환하는 자극과 함께

T 세포 활성화 및 증식을 효과적으로 억제했습니다 [42,43,44].

염증 매개체의 존재 유무에 따른 MSC의 이러한 특정 성능을

MSC 분극화라고 합니다.

MSC는

전신 주입 후 손상된 부위로 이동하여

다양한 기전, 주로 면역 조절 및 혈관 신생에 의해 유익한 효과를 발휘할 수 있습니다 [45, 46].

관련 메커니즘을 매개로 한 MSC 면역 억제는 완전히 밝혀지지는 않았지만,

여러 요인과 함께 세포 상호 작용이

이 과정에서 주요 기능을 수행하는 것으로 보입니다.

높은 수준의 염증성 사이토카인(예: TNF-α 및 IFN-γ)이 존재하는 경우,

MSC는 TGF-β 및 간세포 성장 인자(HGF)를 포함한 여러 사이토카인을 방출하고

인돌아민 2,3-다이옥시제(IDO),

PGE2 및 산화질소(NO) 등의 가용성 인자를 생성합니다.

이러한 매개체는

T 이펙터 세포를 억제하고

조절 T 세포(Treg)에서 FOXP3, CTLA4 및 GITR의 발현을 강화하여

면역 조절 효과를 높입니다 [47,48,49].

또한,

세포 간 통신은

사이토카인 프라이밍 MSC에 의한 Tregs의 자극을 촉진합니다 [50].

유도 가능한 공동 자극기 리간드(ICOSL)의 과발현은

효율적인 Tregs의 자극을 유도합니다 [51].

또한,

MSC는 간접적으로

Treg 세포의 생성을 향상시킬 수 있습니다.

문헌에 따르면,

MSC는 시험관 내 연구에서 M2 대식세포를 자극하고

세포 외 소포 분비를 통해 표현형을 변화시킨다고 합니다 [52].

또한,

MSC에 의해 활성화된 M2 세포는 CCL-18을 발현하고

Treg 세포를 유도합니다 [53].

또한,

MSC는

사이클로옥시게나제 2 (COX2) 및 IDO의 발현을 증가시켜

M2 세포에서 CD206 및 CD163의 발현을 증가시킬 뿐만 아니라

미세 환경에서 IL-6 및 IL-10의 발현을 향상시킵니다 [54].

수지상세포(DC)와 M2 세포의 공동 배양에서 생성되는

IL-10의 과발현은

이펙터 T 세포의 억제를 통해 추가적인 면역조절로 이어집니다 [55, 56].

또한,

MSC에서 분비되는 IDO는

B 세포의 증식, 활성화 및 IgG 방출을 유도하여 T 이펙터 세포를

억제할 수 있습니다 [57, 58].

MSC의 전형적인 특성 중 하나는 이

러한 줄기세포가 체외에서 여러 조직으로 분화할 수 있는

다능성 능력입니다 [59].

시험관 내에서 MSC의 연골 분화는

일반적으로 TGF-β1 또는 TGF-β3, IGF-1, FGF-2 또는 BMP-2가 존재하는 상태에서

배양을 통해 발생합니다 [60,61,62,63].

MSC가

연골세포로 분화하면

콜라겐 II형, IX, 아그레칸 등 다양한 유전자가 증가하고

연골세포 세포 형태가 증식하는 것이 특징입니다.

연골 형성 과정에서

FGF-2는 TGF-β1 또는 TGF-β3 및/또는 IGF-1로 유도된 MSC를 촉진합니다 [64].

문헌 연구에 따르면

고슴도치, Wnt/β-카테닌, TGF-β, BMP 및 FGF와 같은 여러 분자 경로가

연골 형성을 조절할 수 있습니다 [65].

또한

아스코르브산,

β-글리세로인산,

비타민 D3 및/또는 BMP-2, BMP-4, BMP-6 및 BMP-7로 MSC를 유도하여

골 형성 기능을 발휘할 수 있습니다 [66].

중간엽줄기세포의 주요 능력 중 하나는

항섬유화 활동입니다.

이 세포는

생체 내 및 시험관 내에서 간세포와 같은

다양한 세포 계통으로 분화할 수 있습니다 [67].

MSC에는

세포와 매트릭스 리모델링을 유도하여 전구세포와 손상된 세포의 회복을 촉진하는

여러 영양 인자가 포함되어 있습니다.

MSC는

근섬유아세포를 감소시키고

손상된 조직의 섬유화 활동을 역전시킬 수 있습니다 [68].

또한,

이러한 세포는 조직 기능 회복에 관여하는

VEGF, IGF-1 및 항염증 인자를 포함한

혈관 신생 인자를 방출합니다.

예를 들어,

MSC는 심장 질환 마우스 모델에서 VEGF를 통해 허혈성 심근의 신생 혈관 형성을 증가시킬 수 있으며 [69];

또한 IGF-1은 심근 세포의 생존과 증식에 유리한 효과를 발휘합니다 [70].

Bone marrow mesenchymal stem cell-based regenerative medicine

So far, increasing data have lately studied the effects of MSCs in the treatment or regeneration of various disorders (Table 1). In this section, we reviewed the latest clinical studies that investigate the potential contribution of MSCs in the regenerative medicine, as shown in Fig. 1.

골수 중간엽 줄기세포 기반 재생 의학

최근 다양한 질환의 치료 또는 재생에 대한 중간엽줄기세포의 효과를 연구한 데이터가 증가하고 있습니다(표 1). 이 섹션에서는 그림 1 과 같이 재생 의학에서 MSC의 잠재적 기여도를 조사하는 최신 임상 연구를 검토했습니다.

Table 1 Clinical application of bone marrow mesenchymal stem cells in regenerative medicine

Full size table

Fig. 1

Effect of bone marrow mesenchymal stem cell-based regenerative medicine

Neural regeneration

The application of BMSCs has demonstrated promising therapeutic results in the treatment of neurological diseases. Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a neurodegenerative disorder that leads to degeneration of the motor neurons that causes paralysis and muscle weakness [138, 139]. Syková et al. [71] carried out a study that intrathecally injected 15 ± 4.5 × 106 autologous BMSCs into 26 patients with ALS. After mesenchymal stem cells transplantation (MSCT), ALS functional rating scale (ALSFRS) significantly reduced, forced vital capacity (FVC) remained stable or above 70%, and weakness scales (WSs) were stable in 75% of patients. They have shown that the intrathecal BMSCs intervention in ALS patients is a safe method and it can slow down the development of the disease. There were no significant adverse events related to the trial during and after transplantation of BMSCs. Barczewska and colleagues indicated that three intrathecal injections of 30 × 106 Wharton’s jelly-MSCs (WJ-MSCs) improved ALSFRS [77].

신경 재생

BMSC의 적용은

신경 질환 치료에 있어 유망한 치료 결과를 보여주었습니다.

운동 뉴런 질환으로도 알려진 근위축성 측삭 경화증(ALS)은

운동 뉴런의 퇴행으로 마비와 근육 약화를 유발하는 신경 퇴행성 질환입니다 [138, 139].

Syková 등[71]은 루게릭병 환자 26명에게 15 ± 4.5 × 106개의 자가 BMSC를 체내에 주입하는 연구를 수행했습니다.

중간엽 줄기세포 이식(MSCT) 후

루게릭병 기능 평가 척도(ALSFRS)가 유의하게 감소하고

강제 폐활량(FVC)이 안정적이거나 70% 이상으로 유지되었으며

환자의 75%에서 쇠약 척도(WS)가 안정적이었습니다.

연구팀은

루게릭병 환자에 대한 척수강 내 BMSC 개입이 안전한 방법이며

질병의 진행을 늦출 수 있음을 보여주었습니다. B

MSC 이식 중 및 이식 후 임상시험과 관련된 중대한 부작용은 없었습니다.

Barczewska와 동료들은 30 × 106개의 와튼 젤리-MSC(WJ-MSC)를 세 번 척수강 내에 주사한 결과 ALSFRS가 개선되었다고 밝혔습니다 [77].

They showed that WJ-MSCs are safe and effective in individuals that suffer from ALS. However, one other group found that intrathecal injection of autologous adipose MSCs does not improve clinical symptoms of ALS patients [76]. Their results indicated that the levels of CSF protein and nucleated cells were increased and ALSFRS-R showed development of disease in all treated patients. In the trial by OH et al., autologous BMSCs were injected to treat seven participants that suffer from ALS [75]. The participants were injected twice with autologous BMSCs (one million cells per kg) and followed up for 12 months. No serious adverse events were reported during the follow-up period. Furthermore, during the 12-month follow-up, there was no acceleration in the decrease in the ALSFRS-Revised (ALSFRS-R) score, Appel ALS score, and FVC. Moreover, CSF analysis showed that the levels of TGF-β and IL-10 were eval‎uated, while MCP-1, which is chemokine-related and exacerbates the motor neuron damage in ALS, was decreased. Their results exhibited that two repeated MSC infusions have safety and feasibility for at least 1 year in seven individuals; nevertheless, the study has some limitations such as low number of participants and short-time follow-up. In another study [73], 15 ALS patients were transplanted with autologous BMSCs. These 15 patients were divided into two groups (group 1: patients who had ALS with an inherently slow course, group 2: individuals who had ALS with an inherently rapid course) and received three intrathecal infusions of MSCs. There were no significant adverse events in the course of multiple intrathecal injections of MSCs. In group 1, there were no major changes in the rate of disease development and in group 2 ameliorating of the disease was indicated following MSCs therapy. According to their observation, the response of patients with ALS to treatment with MSCs was variable. Also, the authors indicated that due to the small number of patients, less subgroups were available for statistical analysis, limiting their ability to draw conclusions from the data.

연구진은 루게릭병 환자에게 WJ-MSC가 안전하고 효과적이라는 것을 보여주었습니다. 그러나 다른 한 그룹에서는 자가 지방 MSC의 척수강 내 주사가 루게릭병 환자의 임상 증상을 개선하지 못한다는 사실을 발견했습니다 [76]. 그들의 연구 결과에 따르면 CSF 단백질과 핵 형성 세포의 수치가 증가했으며, 치료받은 모든 환자에서 ALSFRS-R이 질병의 발병을 나타냈습니다. OH 등의 임상시험에서는 루게릭병을 앓고 있는 7명의 참가자를 치료하기 위해 자가 BMSC를 주입했습니다 [75]. 참가자들은 자가 BMSC(kg당 100만 세포)를 두 번 주사하고 12개월 동안 추적 관찰했습니다. 추적 관찰 기간 동안 심각한 부작용은 보고되지 않았습니다. 또한 12개월의 추적 관찰 기간 동안 ALSFRS-R 개정판(ALSFRS-R) 점수, Appel ALS 점수 및 FVC의 감소가 가속화되지 않았습니다. 또한 CSF 분석 결과, TGF-β와 IL-10의 수치는 증가한 반면, 케모카인과 관련이 있고 루게릭병의 운동 신경세포 손상을 악화시키는 MCP-1은 감소한 것으로 나타났습니다. 연구 결과, 7명의 환자에서 2회의 반복적인 MSC 주입이 최소 1년간 안전성과 타당성이 있는 것으로 나타났지만, 참여자 수가 적고 추적 관찰 기간이 짧다는 한계가 있습니다. 또 다른 연구 [73]에서는 15명의 루게릭병 환자에게 자가 BMSC를 이식했습니다. 이 15명의 환자는 두 그룹(그룹 1: 본질적으로 느린 경과의 루게릭병 환자, 그룹 2: 본질적으로 빠른 경과의 루게릭병 환자)으로 나뉘어 세 차례에 걸쳐 척수강내 중간엽줄기세포를 주입받았습니다. MSC를 여러 차례 척수강 내에 주입하는 과정에서 중대한 부작용은 없었습니다. 1그룹에서는 질병 발생률에 큰 변화가 없었고, 2그룹에서는 MSC 치료 후 질병이 호전된 것으로 나타났습니다. 연구진이 관찰한 바에 따르면 루게릭병 환자의 MSC 치료에 대한 반응은 다양했습니다. 또한 저자들은 환자 수가 적기 때문에 통계 분석에 사용할 수 있는 하위 그룹이 적어 데이터에서 결론을 도출하는 데 한계가 있다고 지적했습니다.

Spinal cord injury (SCI) is usually related to devastating results. The damage to the spinal cord leads to injury to the motor, sensory, and autonomic roles of the spinal cord that affects patients’ well-being such as their physical and psychological state [140, 141]. In a phase I, nonrandomized, uncontrolled study by Mendonça et al. [84], 15 SCI patients were administered 1 × 107 cells/ml MSCs. The results of the investigation revealed that SCI symptoms were meaningfully decreased by MSCT, all participants showed variable improvements in tactile sensitivity, and eight participants improved lower limb motor functional gains, chiefly in the hip flexors. Seven patients revealed sacral sparing and developed American Spinal Injury Association impairment scale (AIS) grades B or C – partial damage. Nine participants had developments in urologic function and one patient showed alterations in somatosensory evoked potentials (SSEP) 3 and 6 months after MSCT. These results stated that treatment with MSCs ameliorated the organ malfunction in people with SCI and has clinical safety, because no serious adverse effects were reported. The authors indicated that their results should be confirmed in larger and controlled clinical trials. Albu and colleagues have been demonstrated that intrathecal administration of WJ-MSCs considerably improved the pinprick sensation in the dermatomes below the level of damage [88].

척수 손상(SCI)은 일반적으로 치명적인 결과와 관련이 있습니다. 척수 손상은 척수의 운동, 감각 및 자율적 역할에 손상을 입혀 환자의 신체적, 심리적 상태와 같은 웰빙에 영향을 미칩니다[140, 141]. 멘돈사 등[84]의 1상, 비무작위, 비대조군 연구에서 15명의 SCI 환자에게 1 × 107 세포/ml MSC를 투여했습니다. 조사 결과, MSCT를 통해 SCI 증상이 의미 있게 감소하고 모든 참가자가 촉각 민감도가 다양하게 개선되었으며 8명의 참가자가 주로 고관절 굴곡근에서 하지 운동 기능이 개선된 것으로 나타났습니다. 7명의 환자에서 천골이 보존되었고 미국 척추 손상 협회 손상 척도(AIS) 등급 B 또는 C(부분 손상)가 발생했습니다. 9명의 참가자는 비뇨기과 기능에 변화가 나타났고, 한 명의 환자는 MSCT 후 3개월과 6개월 후에 체성감각유발전위(SSEP)에 변화가 나타났습니다. 이러한 결과는 중간엽줄기세포 치료가 SCI 환자의 장기 기능 장애를 개선하고 심각한 부작용이 보고되지 않아 임상적 안전성이 있음을 보여주었습니다. 저자들은 더 크고 통제된 임상시험을 통해 결과를 확인해야 한다고 말했습니다. Albu와 동료들은 WJ-MSC의 척수강 내 투여가 손상 수준 이하의 피부에서 핀 찌름 감각을 상당히 개선했음을 입증했습니다 [88].

Further results showed that bladder maximum capacity was elevated and bladder neurogenic hyperactivity and external sphincter dyssynergy were reduced. In another study [85], ten SCI subjects received four subarachnoid injections of 30 × 106 autologous BMSCs, maintained in autologous plasma, at weeks 1, 16, 28, and 40 of the trial and followed up for 12 months. There were no adverse events and all participants tolerated the therapy. Vaquero et al. [86] demonstrated that MSCT is safe and improves sensitivity, motor power, spasms, spasticity, neuropathic pain, sexual function, or sphincter dysfunction in the SCI patients. The results of their study have shown that 55.5% of patients improved in SSEP and 44.4% of patients ameliorated in voluntary muscle contraction together with intralesional active muscle reinnervation. Hur et al. carried out a study in which 14 patients with SCI were administered intrathecally 9 × 107 adipose MSCs [87]. Their observations showed mild progresses in neurological function. No serious adverse events were observed. In a phase 2 study, 13 patients with SCI were intravenously administered a single dose of autologous MSCs cultured in auto-serum [82]. The results of this trial revealed that SCI symptoms were considerably declined by MSC therapy, ASI, International Standards for Neurological and Functional Classification of Spinal Cord (ISCSCI-92), and Spinal Cord Independence Measure (SCIM-III) demonstrated functional improvements after MSC injection. No severe adverse effects were related to MSC administration.

추가 결과 방광 최대 용량이 증가하고 방광 신경성 과잉 활동과 외부 괄약근 부조화가 감소한 것으로 나타났습니다. 또 다른 연구[85]에서는 10명의 SCI 피험자가 시험 1, 16, 28, 40주차에 자가 혈장으로 유지된 30 × 106개의 자가 BMSC를 지주막하로 4회 주사하고 12개월 동안 추적 관찰했습니다. 부작용은 없었으며 모든 참가자가 치료를 견뎌냈습니다. Vaquero 등[86]은 MSCT가 안전하며 SCI 환자의 민감도, 운동 능력, 경련, 경직, 신경병증성 통증, 성 기능 또는 괄약근 기능 장애를 개선한다는 것을 입증했습니다. 연구 결과에 따르면 환자의 55.5%가 SSEP에서 개선되었고 44.4%의 환자가 병변 내 활성 근육 재신경화와 함께 자발적 근육 수축이 개선되었습니다. Hur 등은 SCI 환자 14명에게 9 × 107 지방 MSC를 척수강 내로 투여하는 연구를 수행했습니다 [87]. 그들의 관찰 결과 신경 기능이 경미하게 개선된 것으로 나타났습니다. 심각한 부작용은 관찰되지 않았습니다. 2상 임상시험에서는 SCI 환자 13명에게 자가 혈청에서 배양한 자가 MSC를 단일 용량으로 정맥 투여했습니다 [82]. 이 임상시험의 결과, MSC 치료로 SCI 증상이 상당히 감소했으며, 척수의 신경학적 및 기능적 분류를 위한 국제 표준(ISCSCI-92)과 척수 독립성 측정(SCIM-III)에서도 MSC 주입 후 기능적 개선이 입증되었습니다. MSC 투여와 관련된 심각한 부작용은 나타나지 않았습니다.

Parkinson’s disease (PD) is a neurological disorder principally characterized by the deterioration of motor activities due to the impairment of the dopaminergic nigrostriatal system [142, 143]. It has been indicated that MSCs improved the symptoms of PD. In a phase I controlled, randomized clinical study, patients that suffer from progressive supranuclear palsy were administered autologous BMSCs via intra-arterial injection [78]. The results of the study exhibited that autologous BMSCs are safe and reduce disease progression. Canesi et al. [79] have demonstrated that injection of MSCs into cerebral arteries of PD patients led to positive results in 17 PD participants: all treated participants were alive and motor function rating scales remained stable for at least 6 months during the 12-month follow-up period. One patient died 9 months after the injection for reasons not associated with cell infusion or to disease development.

파킨슨병(PD)은

주로 도파민성 흑질 시스템의 손상으로 인한

운동 활동의 악화를 특징으로 하는 신경학적 장애입니다 [142, 143].

MSC가

파킨슨병의 증상을 개선하는 것으로 나타났습니다.

1상 대조군 무작위 임상 연구에서 진행성 핵상 마비를 앓고 있는 환자에게

동맥 내 주사를 통해 자가 BMSC를 투여했습니다 [78].

연구 결과, 자가 BMSC는 안전하고 질병 진행을 감소시키는 것으로 나타났습니다.

Canesi 등[79]은

17명의 파킨슨병 환자에게 MSC를 뇌동맥에 주입한 결과,

모든 치료 참가자가 생존했고

12개월 추적 관찰 기간 동안 운동 기능 평가 척도가

최소 6개월 동안 안정적으로 유지되는 긍정적인 결과를 얻었음을 입증했습니다.

한 명의 환자는 세포 주입 또는 질병 발병과 관련이 없는 이유로 주사 후 9개월 후에 사망했습니다.

In a study conducted by Jaillard and colleagues in 2019 [89], 31 individuals with subacute stroke were administered the intravenous injections of autologous BMSCs. The results of the trial exhibited significant improvements in motor-National Institute of the Health Stroke Scale (NIHSS) score, motor-Fugl-Meyer scores, and task-related functional MRI activity in motor cortex-4a. However, there was no remarkable progress in Barthel Index, NIHSS, and modified Rankin scores. In general, their results suggested that BMSCs improved motor recovery via sensorimotor neuroplasticity. In another study, 17 patients with subacute middle cerebral artery infarct received two million cells/kg autologous BMSCs [92]. During the follow-up process, NIHSS score, modified Rankin Scale or Barthel Index did not improve after the transplantation. Nonetheless, there was a significant improvement in absolute change in median infarct volume, but no treatment-related adverse effects were observed.

In sum, these outcomes suppose that BMSCs can safely and efficiently treat neural diseases, inhibit disease development, and considerably ameliorate the quality of life and clinical manifestations of patients. Consequently, BMSCs can become a new option for the clinical treatment of neural diseases.

2019년에 Jaillard와 동료들이 실시한 연구[89]에서 31명의 아급성 뇌졸중 환자에게 자가 BMSC 정맥 주사를 투여했습니다. 임상시험 결과, 운동-국립보건원 뇌졸중 척도(NIHSS) 점수, 운동-푸글-마이어 점수, 운동 피질-4a의 과제 관련 기능적 MRI 활동이 크게 개선된 것으로 나타났습니다. 그러나 바텔 지수, NIHSS, 수정 랭킨 점수에서는 눈에 띄는 진전이 없었습니다. 일반적으로 연구 결과는 BMSC가 감각 운동 신경 가소성을 통해 운동 회복을 개선한다는 것을 시사했습니다. 또 다른 연구에서는 아급성 중대뇌동맥 경색 환자 17명에게 200만 세포/kg의 자가 BMSC를 투여했습니다[92]. 추적 관찰 과정에서 이식 후 NIHSS 점수, 수정된 랭킨 척도 또는 바텔 지수는 개선되지 않았습니다. 그럼에도 불구하고 경색 중앙값의 절대적인 변화는 크게 개선되었지만 치료와 관련된 부작용은 관찰되지 않았습니다.

요약하면, 이러한 결과는 BMSC가 안전하고 효율적으로 신경 질환을 치료하고 질병의 진행을 억제하며 환자의 삶의 질과 임상 증상을 상당히 개선할 수 있음을 시사합니다. 따라서 BMSC는 신경 질환의 임상 치료를 위한 새로운 옵션이 될 수 있습니다.

Liver regeneration

The potential of BMSCs to differentiate into the endodermal lineage, such as hepatocyte‐like cells, makes them an attractive alternative for the treatment of liver diseases [144]. Some clinical studies have demonstrated the efficacy and feasibility of BMSC therapy in patients with liver diseases. The effect of BMSCs has been studied in individuals suffering from liver cirrhosis by Suk et al. [98]. Seventy-two patients were enrolled in this trial and randomly classified into three groups: one control group and two autologous BMSC groups that received one-time or two-time hepatic arterial administrations of fifty million autologous BMSCs 30 days after BM aspiration. Fibrosis quantification exhibited that in one-time and two-time BMSC groups there are a reduction of 25% and 37% in the proportion of collagen, respectively. In addition, the Child–Pugh (CP) scores of both test groups were meaningfully improved following BMSC administration in comparison with the control group. No serious adverse events were associated with MSC injection during the 12-month follow-up. Wang and coworkers have found that intravenous injection of UC-MSCs (0.5 × 106 cells/kg) is feasible and well tolerated in patients with primary biliary cirrhosis (PBC) [93]. They exhibited that MSCs significantly decreased the level of ALP and GGT; however, there were no considerable changes in serum AST, ALT, total bilirubin, albumin, prothrombin time activity, or immunoglobulin M levels. Similarly, Zhang et al. [94] have demonstrated that intravenous administration of 1.0 × 106 cells/kg UC-MSCs is safe and efficient for patients with ischemic-type biliary lesions after liver transplantation. According to their results, MSCs therapy reduced the serum ALP, GGT, and total bilirubin. In a randomized placebo-controlled phase I–II single-center study, nine patients that suffer from acute-on-chronic liver failure (ACLF) grades 2 and 3 were enrolled [95]. The experiment group (n = 4) received standard medical therapy along with five injections of 1 × 106 cells/kg of BMSC for 3 weeks. There were no transplant-related adverse events; however, one patient in the experiment group showed hypernatremia and a gastric ulcer, after the third and fifth administrations, respectively. Furthermore, MSCT revealed a considerable improvement in CP, model for end-stage liver disease (MELD), and ACLF (grade 3 to 0). Thus, MSCT is safe and viable in individuals with ACLF. In an open-label non-blinded randomized controlled study conducted by Lin et al. [96], 110 patients with hepatitis B virus (HBV)-related ACLF were enrolled in this trial. These patients were divided into two groups: control group (N = 54) was treated with standard medical therapy only and the intervention group (N = 56) was injected four times with 1.0–10 × 105 cells/kg allogeneic BMSCs, and then followed up for 6 months. There were no serious adverse events associated with transplantation. The results of that study demonstrated that MSCT significantly improved clinical laboratory measurements, such as serum total bilirubin, and MELD scores in comparison with control group. In addition, mortality from multiple organ failure and preval‎ence rate of serious infection in the intervention group was lower than that in the control group. Their results clearly established the safety and feasibility of the clinical use of peripheral administration of allogeneic BMSCs for subjects with HBV-associated ACLF, and markedly enhanced the survival rate through enhancing liver function and reducing the preval‎ence of severe infections.

In summary, MSCT can meaningfully ameliorate the clinical manifestations of these patients, reduce the liver fibrosis, and inhibit the development of disease.

Kidney regeneration

Hurt to renal cells can occur because of a wide range of ischemic and toxic insults and results in inflammation and cell death, which can lead to kidney damage. Inflammation has a significant role in the damage of renal cells, as well as following cellular regeneration processes [3, 145]. Various investigations have consistently demonstrated a supportive effect of MSC on acute and chronic renal injury [146]. Makhlough et al. declared that intravenous administration of 1–2 × 106 cells/kg into seven patients with chronic kidney disease failed to induce remission [101]. They indicated that variations in estimated glomerular filtration rate (eGFR) and serum creatinine during the 18-month follow-up were not statistically significant. Nonetheless, no severe adverse events were reported, and they could not assess the efficacy because of their study design. Authors postulated that limited sample size and lack of a control group led to the lack of success. A study conducted by Swaminathan et al. in 2021, has displayed the effect of allogeneic BMSCs in acute kidney injury patients. They have shown that treatment of MSCs with SBI-101 stimulated an immunotherapeutic response that initiated an enhanced phenotypic alteration from tissue injury to tissue repair [102]. In a single-arm phase I clinical trial carried out by Makhlough et al. [100], six patients with autosomal dominant polycystic kidney disease (ADPKD) were intravenously injected 2 × 106 cells/kg autologous BMSCs. The results of the study showed that the mean eGFR value declined and the level of serum creatinine enhanced during the 1-year follow-up. Moreover, no remarkable modifications in renal function parameters and blood pressure were observed during the year after intervention. However, there were no severe adverse events after 1-year follow-up. In addition, the authors indicated that there are some reasons for the lack of success, including small number of patients, absence of a comparison group, limited follow-up period, single dose administration, and they did not utilize htTKV as a surrogate endpoint. Abumoawad and colleagues have established that adipose MSCs enhanced blood flow, GFR and reduced inflammatory injury in poststenotic kidneys of individuals that suffer from atherosclerotic renovascular disease (ARVD) [99]. Their results illustrated that mean renal blood flow was considerably enhanced, and hypoxia, renal vein inflammatory cytokines, and angiogenic factors were considerably attenuated.

Heart regeneration

Heart disease is the first and most frequently diagnosed disease and the leading cause of disease death [147]. When cardiomyocytes are damaged via ischemic and other factors, the remaining viable cardiomyocytes have a restricted ability to proliferate and dead cardiomyocytes are changed by non-contractile fibrous tissue, leading to functional impairment that elicits the progression of heart failure. According to the developing number of patients with heart disease, there is a vital need to expand an innovative remedy to rescue deteriorating hearts. Regenerative medicine and cell therapy are the upcoming therapeutic opportunities for heart diseases. According to the literature, the transplantation of BM-derived cells and cardiac stem cells into deteriorating hearts appeared to provide functional benefits [148, 149].

In a study by Yagyu et al. [110], 8 individuals with symptomatic heart failure were infused with BMSCs. During the follow-up period, no serious adverse events were observed. There were no major differences in B-type natriuretic peptide, left ventricular ejection fraction (LVEF), and peak oxygen uptake at 2 months. The results of this study recommend further research regarding the feasibility and efficacy of MSCs. In a study by Gao et al. [107], 116 patients with acute myocardial infarction randomly received an intracoronary injection of WJ-MSCs. They indicated that MSCs therapy elevated the myocardial viability and perfusion within the infarcted territory. In addition, the LVEF was elevated and LV end-systolic volumes and end-diastolic volumes were decreased in the WJ-MSCs group.

Chan et al. demonstrated that intramyocardial infusion of autologous BMSCs in conjunction with transmyocardial revascularization or coronary artery bypass graft surgery was technically feasible and could be performed safely. The results showed that regional contractility in the cell-treated regions improved during the 1-year follow-up; also, the quality of life was improved along with a substantial decrease in angina scores at 12 month post-treatment [104]. In a study by Kaushal et al. [113], 12 participants with hypoplastic left heart syndrome were transplanted with allogeneic human MSCs (2.5 × 105 cells/kg). This study determined the safety, feasibility, and usefulness of MSC administration into the left ventricular myocardium. No serious adverse effects were reported during the trial. Mathiasen et al. observed that after BM-MSCT, left ventricular end-systolic volume was significantly reduced, also LVEF, stroke volume, and myocardial mass remarkably improved [103]. In addition, a major decrease in the amount of scar tissue and quality of life score was observed. No side effects were identified. In a randomized, double-blind, placebo-controlled, multicenter, phase II study, 100 patients with anterior ST elevation myocardial infarction received autologous BMSCs and atorvastatin (ATV) treatment. The results of that study represented the absolute change of LEVF within 12 months, improvement in cardiac function, induction of remodeling and regeneration, and improvement in quality of life [108]. Recently, Celis-Ruiz and coworkers conducted a study in which intravenous administration of adipose MSCs within the first 2 weeks of ischemic stroke onset is safe at 24 months of follow-up [106]. In a study conducted by Hare et al. [112], 37 non-ischemic dilated cardiomyopathy patients were divided into two groups and received 10 × 107 allogeneic and autologous BMSCs. Minnesota Living with Heart Failure Questionnaire score decreased in both groups. The major adverse cardiac event rate was lower in allo vs. auto. Also, TNF-α decreased, to a greater extent in allo vs. auto at 6 months. These results suggested the clinically meaningful efficacy of allogeneic vs. autologous BMSCs in non-ischemic dilated cardiomyopathy patients. Qayyum et al. have found that intra‑myocardial injections of autologous adipose MSCs ameliorated cardiac functions and unchanged exercise capacity, in contrast to deterioration in the placebo group [115].

Levy et al. indicated that after allogeneic BMSCs in patients with chronic stroke, Barthel Index scores increased. Moreover, electrocardiograms, laboratory tests, and computed tomography scans of chest/abdomen/pelvis suggest that BMSCs could alleviate the clinical symptoms in patients with stroke [90].

In sum, BMSC therapy can be an effective, achievable, and safe process that remarkably improves cardiac function and promotes patients’ quality of life.

Bone regeneration

Bone regeneration is a hot topic of research in clinical studies. Bone regeneration is a crucial problem in numerous cases, including bone fracture, defect, osteoarthritis, and osteoporosis, which should be resolved [150,151,152]. Autogenous bone grafts are considered the standard approach for bone formation by means of the participants’ own cells that stimulate osteoinductive, bone conductivity, and histocompatibility in bone diseases [153]. Nevertheless, there are some shortcomings of this procedure such as unpredictable absorption, extended recovery time, and patients commonly experience pain and nerve injury at the harvest area [154,155,156]. With the development of understanding bone tissue biology as well as recent approaches in the improvement in tissue regeneration, the application of MSC has become an attractive subject in augmenting bone tissue forming [157, 158].

In a pilot study by Jayankura and coworkers, allogeneic BMSCs were applied to treat 22 participants with bone fractures [128]. All participants received percutaneous implantation of autologous BMSCs (5 to 10 × 107 cells) into the fracture area. After intervention, Tomographic Union Score (TUS) and Global Disease Eval‎uation (GDE) score were improved, and pain at palpation at the fracture site was reduced. In addition, the ratio of blood samples comprising donor-specific anti-HLA antibodies enhanced at 6 months post-intervention. Three serious cell-related adverse events were reported. In another study by Shim and coworkers [129], intramedullary (4 × 107 cells) and intravenous (2 × 108 cells) infusion of WJ-MSCs in combination with teriparatide showed beneficial results in individuals with osteoporotic vertebral compression fractures. Their observation displayed that the mean visual analog scale, Oswestry Disability Index, and Short Form-36 scores meaningfully improved. They stated that WJ-MSCs in combination with teriparatide are viable and have a clinical profit for fracture healing by stimulating bone architecture.

Several studies investigated the effect of BMSCs in osteoarthritis (OA) patients. Chahal et al. carried out a clinical phase I/IIa trial that involved 12 individuals with late-stage Kellgren–Lawrence knee OA. These 12 patients were injected with a single intra-articular of 1 × 106, 10 × 106, and 50 × 106 BMSCs. The results showed that patients had improved Knee Injury and Osteoarthritis Outcome Score (KOOS) pain, symptoms, quality of life, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) stiffness relative to baseline. Moreover, cartilage catabolic biomarkers and MRI synovitis were meaningfully lower at higher doses and the levels of pro-inflammatory monocytes/macrophages and IL-2 reduced in the synovial fluid after intervention. No serious events had occurred [116]. Dilogo et al. have reported that UC-MSCs (10 × 106 cells) significantly decreased the WOMAC and could be a potentially new regenerative treatment for patients with knee OA [127]. In a study conducted by Hernigou et al. [117], 140 patients with OA received a subchondral infusion of BMSCs on one side and received total knee arthroplasty (TKA) on the contralateral knee. They demonstrated that subchondral MSCs had a significant effect on pain to postpone or avoid the TKA in the contralateral joint of patients with OA. In a phase II multicenter randomized controlled clinical trial, 60 OA patients received 10 × 107 cells of autologous BMSCs along with platelet-rich plasma and followed up for 12 months [119]. No serious adverse effects were observed after MSCs injection or during follow‑up. According to the observations, treatment with BMSC related to platelet-rich plasma was demonstrated to be a feasible alternative treatment for individuals with OA, along with clinical development at the end of follow-up. Similarly, Bastos et al. have reported that MSCs alone or in combination with platelet-rich plasma are safe and have an advantageous effect on symptoms in OA individuals [121]. They found that MSCs group and MSCs + platelet-rich plasma group can improve the pain, function and daily living activities, and quality of life subscales. Ten adverse events were reported in three participants in the MSCs group and in two of the MSCs + platelet-rich plasma group. PERS and colleagues reported another clinical phase Ia study that involved 19 individuals suffering from knee OA [123]. These 18 individuals were classified into three groups and received a single intra-articular administration of 2 × 106, 10 × 106, and 50 × 106 adipose MSCs. According to their results, individuals had experienced significant improvement in pain levels and function. There were no severe adverse events; however, 4 individuals experienced transient knee joint pain and swelling after local administration. In a long-term follow-up of a multicenter randomized controlled clinical trial by Espinosa et al. [120], 30 OA patients were administered the intra-articular infusion of two diverse doses of autologous BMSCs cells (10 × 106 or 10 × 107) versus hyaluronic acid in the treatment of OA. No adverse effects occurred after MSCT or during the 4-year follow‑up. Their results showed that intra-articular infusion of BMSCs together with hyaluronic acid is a safe and viable process that leads to a clinical and functional improvement in knee OA.

Overall, these data display that BMSCs can be a promising, safe and effective alternative for bone regeneration, significantly improve the clinical manifestation of patients, and inhibit development of diseases.

Wound regeneration

The skin has several layers along with different compounds and roles that work together to support internal organs and serve various biological roles. It has three main layers, the epidermis, the dermis, and the subcutaneous layer [159]. Generally, skin wound healing, triggered by tissue injury, includes four stages: hemostasis, inflammation, proliferation, and maturation. MSCs can assist in all stages of the wound healing process. The use of MSCs for the treatment of skin can improve the regeneration of skin and reduce scarring. MSCs exert their functions through migration into the skin damage site, suppressing inflammation, and increasing the growth and differentiation ability of fibroblasts, epidermal cells, and endothelial cells [160, 161]. As MSCs have exhibited wound healing in many preclinical studies, the application of MSCs for chronic wounds contributes to progress toward clinical trials. Falanga et al. have demonstrated that autologous BMSCs are an impressive and safe treatment method for wound healing [131]. The results of the study indicated a trend toward a reduction in ulcer size or complete wound closure by 4–5 months. No adverse events were noted. In a study by Zhou et al., 346 patients with skin wounds were administered adipose MSCs [132]. There were no adverse events during the trial. They reported that the granulation tissue coverage rate and thickness of granulation tissue were considerably ameliorated. In an open-label phase I/II study, sixteen participants with vocal fold scarring were administered a single dose of 0.5–2 × 106 cells autologous MSCs [137]. Video ratings of vocal fold vibrations and digitized analysis of high-speed laryngoscopy and phonation pressure threshold were considerably enhanced for 62–75% of the participants. Voice Handicap Index was meaningfully enhanced in eight participants, with the remaining experiencing no remarkable alteration. No serious adverse events or minor side effects were reported. Lonardi et al. observed that micro-fragmented adipose tissue improved skin tropism in patients with diabetic foot ulcer [135]. Furthermore, the results of studies have shown that adipose-derived stem cells had a beneficial effect on the full-thickness foot dorsal skin wound in diabetic mice with a considerably decreased ulcer area [162]. Recently, Huang et al. carried out a clinical study in which six subjects with intrauterine adhesion and four with cesarean scar diverticulum enrolled in this trial [136]. They found that intrauterine injection of UC-MSCs improved the endometrial thickness, cesarean scar diverticulum, and the volume of the uterus.

Conclusion

In the last decades, optimizations of isolation, culture, and differentiation procedures have permitted MSCs to improve closer to clinical uses for improving disorders and various tissue regeneration. MSCs have some important characteristics that make them preferred candidates to use for regenerative medicine: immunomodulatory capability valuable to improve immune system abnormalities, paracrine or autocrine roles that produce growth factors, and the vital potential to differentiate into various cells. Several clinical trials have reported that both autologous and allogeneic MSCs are valuable sources for tissue forming. Particularly, autologous MSCs signify the chief sources examined safe for administration and minimization of immunological threat, regardless of the lack of reported grievances concerning allogeneic MSC-based therapy. According to the studies described in this literature, administration of MSCs appear to be more effective and the usefulness of MSC therapy in bone and heart disorders has been broadly established. In terms of safety, no significant relationship was found between the MSC therapy and incidence of cancer and infection. Intravenous injection of MSCs is the most widely used form of administration and the dosage commonly fluctuates between 1 × 106 cells/kg and 2 × 108 cells/kg. According to the literature works mentioned in this review, the repeated administration of MSCs suggests being more beneficial than a single injection. In addition, the effectiveness of MSCs therapy in osteoarthritis disorder has been widely established. Long-term follow-up studies exhibited that serum tumor markers did not enhance before and 3 years after MSCs therapy. Nevertheless, there is still a lack of reliable scientific data on the mechanisms whereby the MSC therapy improves the numerous disorders that can develop the MSC modification and increase their prospective clinical application.

결론
지난 수십 년 동안 분리, 배양 및 분화 절차의 최적화를 통해 MSC는 질환 개선 및 다양한 조직 재생을 위한 임상적 용도에 더 가깝게 발전할 수 있었습니다. MSC는 면역계 이상을 개선하는 데 유용한 면역 조절 기능, 성장 인자를 생성하는 파라크린 또는 자율신경 역할, 다양한 세포로 분화할 수 있는 중요한 잠재력 등 재생 의학에 사용하기에 선호되는 몇 가지 중요한 특성을 가지고 있습니다. 여러 임상시험에서 자가 및 동종 MSC 모두 조직 형성을 위한 귀중한 공급원이라는 사실이 보고되었습니다. 특히 자가 MSC는 동종 MSC 기반 치료와 관련하여 보고된 불만 사항이 없음에도 불구하고 면역학적 위협을 최소화하고 투여하기에 안전한 것으로 조사된 주요 공급원을 의미합니다. 이 문헌에 기술된 연구에 따르면, 골 및 심장 질환에서 MSC 투여가 더 효과적인 것으로 보이며, MSC 치료의 유용성은 광범위하게 확립되었습니다. 안전성 측면에서는 MSC 치료와 암 및 감염 발생률 사이에 유의미한 관계가 발견되지 않았습니다. 정맥 주사는 가장 널리 사용되는 투여 형태이며 용량은 일반적으로 1 × 106 세포 / kg에서 2 × 108 세포 / kg 사이에서 변동합니다. 이 리뷰에 언급된 문헌 연구에 따르면, MSC를 반복 투여하는 것이 한 번 주사하는 것보다 더 유익한 것으로 나타났습니다. 또한 골관절염 장애에 대한 MSC 치료의 효과는 널리 확립되어 있습니다. 장기 추적 연구에 따르면 혈청 종양 표지자는 MSCs 치료 전과 3년 후에도 개선되지 않는 것으로 나타났습니다. 그럼에도 불구하고 아직까지 MSC 치료가 다양한 질환을 개선하는 메커니즘에 대한 신뢰할 수 있는 과학적 데이터가 부족하여 향후 임상 적용 가능성이 높지 않습니다.

Availability of data and materials

Not applicable.

Abbreviations

ALS :

Amyotrophic lateral sclerosis

AIS :

Association impairment scale

ALSFRS :

ALS functional rating scale

ALSFRS-R :

ALSFRS-revised

ACLF :

Acute-on-chronic liver failure

ADPKD :

Autosomal dominant polycystic kidney disease

ATV :

Atorvastatin

BM :

Bone marrow

BMSCs :

Bone marrow mesenchymal stem cells

COX2 :

Cyclooxygenase 2

CP :

Child–Pugh

DCs :

Dendritic cells

ESCs :

Embryonic stem cells

eGFR :

Estimated glomerular filtration rate

FVC :

Forced vital capacity

GDE :

Global Disease Eval‎uation

HSCs :

Hematopoietic stem cells

HBV :

Hepatitis B virus

HGF :

Hepatocyte growth factor

IPSCs :

Induced pluripotent stem cells

IDO :

Indoleamine 2,3-dioxygenase

ICOSL :

Inducible co-stimulator ligands

ISCSCI-92 :

International Standards for Neurological and Functional Classification of Spinal Cord

KOOS :

Knee injury and osteoarthritis outcome score

LVEF :

Left ventricular ejection fraction

MiRNAs :

MicroRNAs

MSCs:

Mesenchymal stem cells

MSCT:

Mesenchymal stem cells transplantation

MELD:

Model for end-stage liver disease

NO:

Nitric oxide

OA:

Osteoarthritis

PSCs:

Pluripotent stem cells

PGE2:

Prostaglandin E2

SCI:

Spinal cord injury

SSEP:

Somatosensory evoked potentials

SCIM-III:

Spinal cord independence measure

Tregs:

Regulatory T cells

TUS:

Tomographic Union Score

TKA:

Total knee arthroplasty

WSs:

Weakness scales

WOMAC:

Western Ontario and McMaster Universities Osteoarthritis Index

References

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