**1. Introduction**

Mesenchymal stem/stromal cells (MSCs) have been acknowledged as medicinal signaling cells as well as the most important niche cells in the microenvironment, and possess advantaged properties such as immunomodulatory capacity, hematopoietic-supporting effect and multi-lineage differentiation potential towards adipocytes, osteoblasts and chondrocytes, which thus hold promising prospects for tissue engineering and regenerative medicine [1–3]. MSCs were first isolated from bone marrow in the 1960s, and followed by various stromal fractions of adult tissues [4, 5], perinatal tissues [6–8], and even derived from stem cells [9–11]. For decades, due to the limitation of unique biomarkers and the wide range of cell sources, MSCs

are recognized as heterogeneous populations with great heterogeneity in cellular phenotypes and transcriptome characteristics [12–14]. Generally, MSCs with diverse origins mainly function via direct- or trans-differentiation, paracrine or autocrine, homing, dual immunomodulation, neovascularization, and constitutive microenvironment [4, 15, 16]. To date, more than 1340 MSC-based clinical trials have been registered for various disease treatment according to the ClinicalTrials. gov website. For instance, we and other investigators have indicated the therapeutic effects of MSCs upon multiple refractory and recurrent disorders including acute graft-versus-host diseases (aGVHD) [17], aplastic anemia [18, 19], osteoarthritis [11, 20], critical limb ischemia (CLI) [9], acute-on-chronic liver failure (ACLF) [21], Parkinson's syndrome [22], acute myocardial infarction (AMI) [23], rheumatoid arthritis (RA) [24], and coronavirus disease 2019 (COVID-19) [15, 25]. It's noteworthy that the variation of the therapeutic efficacy of MSCs upon acute liver failure and aGVHD has also been respectively observed by Zhang et al. and us, which further indicated the necessity and urgency of developing tissue engineering including biomaterials, three-dimensional (3D) printing, and MSC-based gene therapy [26, 27].

Simultaneously, state-of-the-art updates have further suggested the preferable application of biomaterial/MSC composite as well [11, 28, 29]. Of the current natural extracellular matrices (ECMs), hydrogels have been regarded as the most promising alternative biomaterials attribute to their excellent swelling property and the resemblance to soft tissues [11, 30]. In particular, synthetic biomimetic hydrogels with appropriate mechanical behavior and predictable biodegradation property can be easily synthesized and modulated for facilitating the biological phenotypes and bioapplications of the encapsulated MSCs such as adhesion, migration, differentiation, proliferation, and apoptosis [30]. For instance, Gwon et al. and Huang et al. reported the influence of heparin-hyaluronic acid (HA) hydrogel upon cellular activity and hydrogel scaffolds for the differentiation of adipose-derived stem cells, respectively [30, 31]. Very recently, we took advantage of the HA hydrogel/MSC composite and demonstrated the reinforced cell vitality of human pluripotent stem cell-derived MSCs (hPSC-MSCs) over monolayer-cultured MSCs for chondrogenesis and the management of osteoarthritis rabbits [11].

Herein, we summarize the current progress in MSCs or MSC-derived exosomes and hydrogel scaffold for tissue engineering, and in particular, the potentially reinforcing or attenuating effects of hydrogel scaffold with unique biochemical and biophysical properties upon the MSC-based cytotherapy for regenerative medicine.

### **2. The cell sources of MSCs for tissue engineering**

Not until 2006, the International Society for Cellular Therapy (ISCT) defined the preliminary criteria of defining multipotent MSCs including adherent property, multi-lineage differentiation capacities *in vitro* towards adipocytes, osteoblasts, and chondrocytes, together with high-levels of mesenchymal biomarker expression (CD73, CD90, and CD105) whereas minimal expression of hematopoietic or endothelial markers (CD31, CD34, and CD45) [32]. After that, numerous studies aiming at dissecting the similarities and differences in biological phenotypes and biofunctions as well as transcriptome characteristics of MSCs derived from adult tissue, perinatal tissue, and PSCs have been extensively conducted (**Table 1**).

*Mesenchymal Stem/Stromal Cells and Hydrogel Scaffolds for Tissue Engineering DOI: http://dx.doi.org/10.5772/intechopen.101793*


#### **Table 1.**

*Representative applications of HA/MSC-based scaffold in tissue engineering.*

### **2.1 Adult tissue-derived MSCs**

As mentioned above, adult tissue-derived MSCs hold vast prospect in tissue repairing and organ reconstruction [3]. To date, massive literatures have reported the isolation and identification of MSCs from various adult tissues such as adipose tissue, bone marrow, synovium, dental pulp, peripheral blood, muscle tendon, and menstrual blood [40, 41]. According to the ClinicalTrials.gov website, a total of 1096 trials have been registered worldwide against disorders such as acute respiratory distress syndrome (ARDS), CLI, AMI, anoxic or hypoxic brain injury, moderate-to-severe Crohn's disease, idiopathic pulmonary fibrosis (IPF), and COVID-19. For example, a phase I interventional trial was led by Dr. Jesus JV Vaquero Crespo in Puerta de Hierro University Hospital was aiming to evaluate the security of local administration of autologous bone marrow-derived MSCs (BM-MSCs) in traumatic injuries of the spinal cord (NCT01909154), which was consistent with another study by Geffner and their colleagues [42]. In details, 12 participants received 1 × 108 BM-MSCs by intrathecal injection (subarachnoid and intramedullary), and another 3 × 107 BM-MSCs by subarachnoid administration after 3 months depending on centromedullary post-traumatic injury. The safety outcomes of the patients were evaluated according to vital signs (ECG, blood pressure, and heart rate) and possibility of adverse reaction (headache, meningeal irritation, and infectious complications). The secondary outcomes were quantized from the view of sensitivity recovery (e.g., surface sensitivity and pain sensitivity), level of chronic pain, neurophysiological parameters, maximum cystometric capacity, and the decrease in volume and hyperintensity of intramedullary lesions. Very recently, Oraee-Yazdani et al. further verified that BM-MSCs in combination with autologous Schwann cell co-transplantation was safe and effective for treating 11 patients of spinal cord injury (SCI), and in particular for spinal cord regeneration during subacute period [43].

Notably, cutting-edge advances have also put forward the variations and limitations of adult tissue-derived MSCs in both preclinical and clinical studies [1, 14, 44]. For example, among the indicated adult tissue-derived MSCs, BM-MSCs are recognized as the widest application in clinical practices whereas with inherent disadvantages such as ethical risk, pathogenic risk, invasive pain, replicative senescence and individual diversity for cell source, and in particular, the limitation in healthy donors and declined long-term *ex vivo* amplification further restrict the large-scale application in future [11, 44]. Interestingly, despite the variations in signatures and functions, we recently verified the potential conservative properties in adipose tissue-derived stem cells (AD-MSCs) from type 2 diabetics and healthy donors [4]. However, multifaceted diversity among BM-MSCs, AD-MSCs, dental pulp stem cells (DPSCs), and supernumerary teeth-derived apical papillary stem cells (SCAP-Ss) were observed by investigators in the field [16, 45–47].

#### **2.2 Perinatal tissue-derived MSCs**

Perinatal tissues are abundant sources of MSCs and extracellular matrix with a wide range of therapeutic purposes in tissue engineering, which thus act as particularly interesting candidates for regenerative medicine [48, 49]. To date, a variety of perinatal tissue-derived MSCs have been identified such as placental-derived MSCs (P-MSCs), umbilical cord-derived MSCs (UC-MSCs), cord blood-derived MSCs (CB-MSCs) [49, 50], amniotic-derived MSCs (A-MSCs) [51], amniotic fluid-derived MSCs (AF-MSCs) [52], decidua-derived MSCs (D-MSCs) [53], and chorionic villiderive MSCs (CV-MSCs) [54]. Of the aforementioned perinatal tissue-derived MSCs, UC-MSCs are promising sources with preferable properties in long-term proliferation *in vitro* and immunoregulation, and most of all, without ethical risks and limitation in supply, and thus hold great prospect for large-scale clinical investigation and investigational new drug (IND) purposes [18, 44]. Up to November 11th of 2021, a total of 317 interventional clinical trials have been registered for the administration of numerous refractory diseases by UC-MSC infusion such as diabetic nephropathy, heart failure, perianal fistulas with Crohn's disease, lumbar discogenic pain, chronic obstructive pulmonary disease (COPD), Duchenne muscular dystrophy (DMD), and cerebral hemorrhage sequela (CHS) according to ClinicalTrials.gov website.

Similarly, other types of MSC sources are of equal importance in offering "seeds" for tissue engineering and regenerative medicine (e.g., umbilical cord, placenta, amniotic membrane, and amniotic fluid). For instance, Liu and the colleagues took advantage of A-MSCs and conducted intragastric administration and intraperitoneal injection for the management of hydrogen peroxide-induced premature ovarian failure (POF) model. As expected, POF mice with A-MSC transfusion in bilateral ovaries revealed increased estrogen levels, decreased follicle-stimulating hormone level, and evaluated ovarian index and fertility rate, which collectively suggested the ameliorative effects of MSCs in improving the follicular microenvironment and recovering ovarian function in POF [55].

#### **2.3 Pluripotent stem cell-derived MSCs**

Pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), possess self-renewal and multi-lineage differentiation potential, which thus provide advantaged "seeds" for disease modeling and drug validation as well as unprecedented opportunities for cytotherapy against intractable diseases [56–58]. Since the year of 2005, a number of literatures have reported the generation of MSCs from ESCs and iPSCs [59, 60]. Strikingly, the PSC-derived MSCs

### *Mesenchymal Stem/Stromal Cells and Hydrogel Scaffolds for Tissue Engineering DOI: http://dx.doi.org/10.5772/intechopen.101793*

(PSC-MSCs) revealed multifaceted superiority over those derived from adult tissues such as unlimited source, homogeneity, large-scale generation without pathogenic or ethical risks, and in particular, PSC-MSCs could be used for exploring the early development and molecular mechanism of MSCs [10, 53, 61, 62]. Notably, current studies have suggested the considerable efficacy of MSCs or MSC-derived exosomes in preclinical application including experimental inflammatory bowel disease (IBD) [63, 64], allergic tracheal inflammation (e.g., asthma and anaphylactic rhinitis) [65], experimental autoimmune encephalitis (EAE) of multiple sclerosis [66], lupus nephritis [67], acute colitis [68], kidney fibrosis [69], and hematopoietic reconstitution [70].

Generally, there are three strategies for PSC-MSC generation including monolayer induction, PSCs and stromal cell coculture and the embryoid body (EB) models. However, most of the existing strategies with drawbacks such as laborious manipulations (e.g., handpicking and scraping), time-consuming (3–8 weeks), low efficacy (approximately 5–20%), cell sorting (e.g., CD73+ and CD105+ ), and serial passages [10, 71, 72]. For instance, Wei et al., Deng et al., Vainieri et al., Wang et al., and Tran et al. reported the elevated generation of PSC-MSCs by modulating intracellular JAK-STAT [9], IKK/NF-κB [73], PDGF-BB [74], bone morphogenetic protein 4 (BMP) [68], and ABB (activin A, 6-bromoindirubin-3′-oxime, and BMP4) [75] signaling pathways in feeder or serum-free model, respectively. Notably, we recently took advantage of the Msh homeobox 2 (MSX2) and small molecule library-based cell programming strategies for high-efficient induction of PSC-MSCs within 2 weeks, respectively [9–11]. Even though the convenience in practice as well as the promising prospects in tissue engineering and regenerative medicine [76, 77], the potential risks of PSCs attribute to genome editing and their inherent characteristics such as tumorigenicity, heterogeneity, and immunogenicity should cause enough attention [56, 78, 79].
